Controlled release formulations of octreotide

ABSTRACT

A formulation of octreotide or pharmaceutically acceptable salts thereof, which provides controlled release of a therapeutically effective amount of octreotide for a period of at least about two months. Methods of treating acromegaly, decreasing growth hormone, decreasing IGF-1, and treating conditions associated with carcinoid tumors and VIPomas by administering a controlled release formulation of octreotide are provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/372,749, filed on Mar. 10, 2006, which claims the benefit of U.S.Provisional Application No. 60/660,930, filed Mar. 11, 2005, the entirecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to an octreotide pharmaceuticalcomposition that can be used to treat individuals affected with hormonaldisorders. The present invention is preferably formulated as acontrolled release formulation.

Acromegaly is a hormonal disorder that results when the pituitary glandproduces excess growth hormone (GH). It most commonly affectsmiddle-aged adults and can result in serious illness and prematuredeath. Once recognized, acromegaly is treatable in most patients, butbecause of its slow and often insidious onset, it frequently is notdiagnosed correctly.

The present invention may be utilized to treat a variety of hormonaldisorders, including acromegaly and gigantism. One of its most commonsymptoms is the abnormal growth of the hands and feet. Gradually, bonychanges alter the patient's facial features: the brow and lower jawprotrude, the nasal bone enlarges, and spacing of the teeth increases.Overgrowth of bone and cartilage often leads to arthritis. When tissuethickens, it may trap nerves, causing carpal tunnel syndrome,characterized by numbness and weakness of the hands. Other symptoms ofacromegaly include thick, coarse, oily skin; skin tags; enlarged lips,nose and tongue; deepening of the voice due to enlarged sinuses andvocal cords; snoring due to upper airway obstruction; excessive sweatingand skin odor; fatigue and weakness; headaches; impaired vision;abnormalities of the menstrual cycle and sometimes breast discharge inwomen; and impotence in men. There may be enlargement of body organs,including the liver, spleen, kidneys and heart.

The most serious health consequences of acromegaly are diabetesmellitus, hypertension, and increased risk of cardiovascular disease.Patients with acromegaly are also at increased risk for polyps of thecolon that can develop into cancer.

When GH-producing tumors occur in childhood, the disease that results iscalled gigantism rather than acromegaly. Fusion of the growth plates ofthe long bones occurs after puberty so that development of excessive GHproduction in adults does not result in increased height. Prolongedexposure to excess GH before fusion of the growth plates causesincreased growth of the long bones and increased height.

Acromegaly is caused by prolonged overproduction of GH by the pituitarygland. The pituitary is a small gland at the base of the brain thatproduces several important hormones to control body functions such asgrowth and development, reproduction, and metabolism. GH is part of acascade of hormones that, as the name implies, regulates the physicalgrowth of the body. This cascade begins in a part of the brain calledthe hypothalamus, which makes hormones that regulate the pituitary. Oneof these, growth hormone-releasing hormone (GHRH), stimulates thepituitary gland to produce GH. Another hypothalamic hormone,somatostatin, inhibits GH production and release. Secretion of GH by thepituitary into the bloodstream causes the production of another hormone,called insulin-like growth factor 1 (IGF-1), in the liver. IGF-1 is thefactor that actually causes the growth of bones and other tissues of thebody. IGF-1, in turn, signals the pituitary to reduce GH production.GHRH, somatostatin, GH, and IGF-1 levels in the body are tightlyregulated by each other and by sleep, exercise, stress, food intake andblood sugar levels. If the pituitary continues to make GH independent ofthe normal regulatory mechanisms, the level of IGF-1 continues to rise,leading to bone growth and organ enlargement. The excess GH also causeschanges in sugar and lipid metabolism and can cause diabetes.

In over 90% of acromegaly patients, the overproduction of GH is causedby a benign tumor of the pituitary gland, called an adenoma. Thesetumors produce excess GH and, as they expand, compress surrounding braintissues, such as the optic nerves. This expansion causes the headachesand visual disturbances that are often symptoms of acromegaly. Inaddition, compression of the surrounding normal pituitary tissue canalter production of other hormones, leading to changes in menstruationand breast discharge in women and impotence in men.

In some patients, acromegaly is caused not by pituitary tumors but bytumors of the pancreas, lungs, and adrenal glands. These tumors alsolead to an excess of GH, either because they produce GH themselves or,more frequently, because they produce GHRH, the hormone that stimulatesthe pituitary to make GH. In these patients, the excess GHRH can bemeasured in the blood and establishes that the cause of the acromegalyis not due to a pituitary defect. When these non-pituitary tumors aresurgically removed, GH levels fall and the symptoms of acromegalyimprove.

Treatment regimens include reducing GH production to normal levels torelieve the pressure that the growing pituitary tumor exerts on thesurrounding brain areas, to preserve normal pituitary function, and toreverse or ameliorate the symptoms of acromegaly. Currently, treatmentoptions include surgical removal of the tumor, drug therapy, andradiation therapy of the pituitary.

SUMMARY OF THE INVENTION

Octreotide is one drug used to treat acromegaly. Octreotide exertspharmacologic actions similar to those of the natural hormonesomatostatin. Octreotide decreases GH and IGF-1 levels, as well asglucagons and insulin. Octreotide also suppresses luteinizing hormone(LH) response to gonadotropin releasing hormone (GnRH), decreasessplanchnic blood flow, and inhibits the release of serotonin, gastrin,vasoactive intestinal peptide, secretin, motilin, and pancreaticpolypeptide. In many patients, GH levels fall within one hour andheadaches improve within minutes after the injection of octreotide.Several studies have shown that octreotide is effective for long-termtreatment. Octreotide also has been used successfully to treat patientswith acromegaly caused by non-pituitary tumors. In some acromegalypatients who already have diabetes, octreotide can reduce the need forinsulin and improve blood sugar control.

Octreotide is currently available as Sandostatin LAR® Depot, which is,upon reconstitution, a suspension of microspheres containing octreotideacetate. Sandostatin LAR® Depot is the only medication indicated for thelong-term maintenance therapy in acromegalic patients. It is alsoindicated for the long-term treatment of severe diarrhea and flushingepisodes associated with metastatic carcinoid tumors and profuse waterdiarrhea associated with VIP-secreting tumors. Sandostatin LAR® T Depotis administered via intramuscular injection every four weeks, followinga titration period. Octreotide acetate has also been available in animmediate-release formulation, Sandostatin® Injection solution, whichwas required to be administered by injection three times daily.

The present invention provides a therapeutically effective amount ofoctreotide over an extended period of time, preferably at least abouttwo months, more preferably about six months and up to about two years.The present invention also provides compositions that provide controlledrelease of octreotide over at least about two months, preferably aboutsix months, and up to about two years.

Embodiments of the present invention relate to a pharmaceuticalcomposition comprising octreotide or salts, prodrugs or derivativesthereof, which can be used in the effective treatment of variousdiseases and conditions, including, but not limited to acromegaly,diabetes, severe diarrhea and flushing episodes associated withcarcinoid tumors and watery diarrhea associated with VIPomas.

In one embodiments of the present invention, a composition including ahydrogel and octreotide is provided. The octreotide may be present as afree base, salt or complex form. The composition is capable ofproviding, upon administration to a patient, a desirable pharmacokineticprofile of octreotide for the condition being treated.

Another embodiment of the present invention is directed to apharmaceutical composition containing octreotide for implantation into apatient. In one embodiment, the implantable composition may furthercomprise a hydrogel, which provides consistent, predetermined, andcontrolled release of octreotide upon subcutaneous implantation underthe skin of a patient. Preferably hydrogels include methacrylate basedpolymers and polyurethane based polymers.

Another embodiment of the present invention is a stable pharmaceuticalcomposition which comprises a therapeutically effective amount ofoctreotide in an implant that provides a pharmacokinetic profile of theoctreotide to a patient that has a desired C_(ss) over an extendedperiod of time. The composition may be used to establish and or maintainin a patient, a therapeutically effective level of octreotide.Preferably octreotide is released over time so that a therapeuticallyeffective level of octreotide in the patient can be achieved over atleast about two months, and more preferably about six months or longer.In a more preferred embodiment, undesirable spikes or peaks in therelease of octreotide are avoided. In preferred embodiments, thepharmaceutical composition comprises octreotide, more preferablyoctreotide acetate, contained within a hydrogel. In another preferredembodiment, the pharmaceutical composition comprises octreotide, morepreferably octreotide acetate, contained within polyurethane basedpolymers, a methacrylate based polymer. The pharmaceutical compositionof the present invention may also comprise one or more pharmaceuticallyacceptable excipients.

Another embodiment of the present invention is a stable, controlledrelease implantable formulation of a composition which includes atherapeutically effective amount of octreotide contained in a polymerreservoir that provides a pharmacokinetic release profile of octreotidein the blood plasma of the patient extending over a period of at leastabout two months, and more preferably about six months or longer.

Preferably, the implantable formulation of the composition is an implantformed by polymerization of hydrophilic monomers of the presentinvention. In preferred embodiments, the implantable formulationincludes a hydrophilic implant of a therapeutically effective amount ofoctreotide, such as octreotide acetate, contained within hydrophiliccopolymers, such as 2-hydroxyethyl methacrylate (HEMA) and hydroxypropylmethacrylate (HPMA). The implant form of the present invention may alsoinclude one or more pharmaceutically acceptable excipients. In a furtherembodiment, the implantable formulation of the composition is an implantformed from polyurethane based polymers.

The octreotide formulations of the present invention impart chemical andphysical stability to the composition while providing a controlledrelease profile. This enhanced stability is most notably observed incompositions and dosage forms of the present invention where thestability of octreotide is achieved while maintaining the desiredcontrolled-release profile. Specifically, the implantable formulationsof the present invention exhibit superior resistance to moistureabsorption, while providing a release profile of octreotide that permitsestablishment of a therapeutically effective concentration of octreotideover an extended period of time, preferably at least two months, morepreferably about six months and up to about two years.

In one embodiment of the present invention, a controlled releaseformulation comprising octreotide that provides an in vivo averageC_(ss) of about 0.1 ng/ml to about 9 ng/ml, more preferably about 1ng/ml to about 2 ng/ml, of octreotide in a patient is provided. In oneembodiment, the formulation contains from about 20 to about 150milligrams of octreotide, more preferably, about 40 to about 90milligrams of octreotide. The formulation may be selected from animplant, a pump, or other similar controlled release device. Inpreferred embodiments, the formulation releases a therapeuticallyeffective amount of octreotide over a period of about two months toabout two years, more preferably about six months to about one year,more preferably about six months.

In further embodiments, the controlled release formulation of octreotidemay comprise a hydrophilic copolymer. Preferred hydrophilic copolymersinclude 2-hydroxyethyl methacrylate and hydroxypropyl methacrylate. Inone embodiment, the copolymer comprises about 20% of 2-hydroxyethylmethacrylate and about 80% hydroxypropylmethacrylate. The formulationmay further comprise magnesium stearate. In another embodiment, theformulation may further comprise hydroxypropylcellulose.

In another embodiment, the controlled release formulation of octreotidemay comprise a polyurethane based polymer.

In another embodiment, a method of treating a patient comprisingadministering a controlled release formulation of octreotide isprovided. In one preferred embodiment, the controlled releaseformulation maintains an in vivo average C_(ss) of about 0.1 ng/ml toabout 9 ng/ml of octreotide in a patient in need thereof.

Another embodiment of the present invention is a method of treatingacromegaly or symptoms associated with acromegaly comprisingadministering a controlled release formulation of octreotide isprovided. Preferably, the controlled release formulation is capable ofmaintains an average C_(max) average of said octreotide at about 0.1ng/ml to about 4 ng/ml for an extended period of time. Preferably theextended period of time is about two months to about two years, morepreferably about six months.

In a further embodiment, a method of treating acromegaly or symptomsassociated with acromegaly comprising administering at least onehydrogel implant comprising between about 40 to about 90 milligrams ofoctreotide, more preferably about 50 milligrams, more preferably about83 milligrams, is provided. In certain methods, one hydrogel implant maybe administered and in other methods two or more hydrogel implants maybe administered. The hydrogel implant(s) may administered every abouttwo months to about two years, preferably about every six months.

A further embodiment of the present invention is a therapeuticcomposition comprising a hydrophilic copolymer and octreotide. In oneembodiment, the octreotide may be released at a rate to maintain aC_(ss) of about 0.1 ng/ml to about 9 ng/ml over at least two months toabout twenty-four months. In one embodiment the hydrophilic copolymercomprises a mixture of an ethylenically unsaturated hydrophilic monomerA and an ethylenically unsaturated hydrophilic monomer B. One preferredmonomer A is 2-hydroxyethyl methacrylate. In one embodiment, thehydrophilic copolymer may comprise from about 15% to about 70%, morepreferably about 20%, of the hydrophilic copolymer. One preferredmonomer B is hydroxypropylmethacrylate. In one embodiment, thehydrophilic copolymer may comprise about 80% of the hydrophiliccopolymer. Such therapeutic compositions are capable of release at arate to maintain a C_(ss) of octreotide of about 1 ng/ml to about 2ng/ml over at least two months to about twenty-four months.

A further embodiment of the present invention provides an implantabledrug delivery device comprising octreotide, wherein said device deliversa therapeutically effective amount of octreotide over at least about twomonths to about twenty-four months. In one embodiment, thetherapeutically effective amount of octreotide is from about 20 μg toabout 800 μg per day. In another embodiment, the therapeuticallyeffective amount of octreotide is from about 30 μg to about 300 μg perday.

Another embodiment of the present invention is a controlled releaseformulation comprising octreotide for implantation, said formulationincluding octreotide in a hydrophilic polymer effective to permitrelease of said octreotide at a rate of about 30 μg to about 250 μg perday, more preferably about at an average rate of about 100 μg per day invitro, over about six months in vitro.

A controlled release formulation comprising octreotide for implantation,said formulation including octreotide in a hydrophilic polymer effectiveto permit in vitro release of: no more than about 20% of said octreotidefrom said formulation after about 6 weeks; and about 60% of saidoctreotide from said formulation after about six months.

In another embodiment of the present invention, an implant comprisingoctreotide, HEMA, HPMA is provided. The implant may further comprisepharmaceutically acceptable excipients, including, for example,hydroxypropylcellulose and/or magnesium stearate.

The compositions of the present invention may be used in the treatmentof a condition in a patient which includes establishing atherapeutically effective concentration of octreotide in the patient inneed thereof. The compositions may be used for building up a level andor maintaining a therapeutically effective concentration of octreotidein the patient by administration, preferably implantation, of thecomposition every about six months. The compositions of the presentinvention may be formulated to avoid large peaks in initial release ofoctreotide. The compositions of the present invention when administeredto a patient in need thereof provide for the treatment of hormonaldiseases that are characterized by increased levels of GH or IGF-1. Inaddition, the compositions of the present invention when administered toa patient in need thereof provide for the treatment of symptomsassociated with carcinoid tumors and VIPomas. Preferably, thecompositions are a stable, controlled release implant containing atherapeutically effective amount of octreotide in a hydrogel, preferablymethacrylate or polyurethane based polymers, such that a therapeuticallyeffective blood plasma level of octreotide is maintained in the patientfor a period of at least about 2 months, preferably at least about 6months, more preferably about 12 months and up to two years.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the linear relationship between theequilibrium water content vs. the weight percent content ofhydroxypropyl methacrylate (HPMA) units in crosslinked HEMA/HPMApolymers at their maximum state of hydration.

FIG. 2 is a graph showing the release of octreotide from an implantformulation of the present invention.

FIG. 3 is a graph showing the release of octreotide from an implantformulation of the present invention.

FIG. 4 is a graph showing the release of octreotide from six differentimplant formulations of the present invention.

FIG. 5 is a graph showing the release of octreotide from differentimplant formulations of the present invention.

FIG. 6 is a graph showing octreotide and IGF-1 serum levels in a healthydog implanted with an octreotide formulation of the present invention.

FIG. 7 is a graph showing octreotide and IGF-1 serum levels in a groupof 3 healthy dogs implanted with one octreotide implant formulation ofthe present invention over a six month period.

FIG. 8 is a graph showing octreotide and IGF-1 serum levels in a groupof 3 healthy dogs implanted with two octreotide implant formulations ofthe present invention over a six month period.

FIGS. 9A and 9B are graphs depicting the IGF-1 serum level and percentchange in eleven human subjects with acromegaly over six monthsimplanted with an octreotide formulation of the present invention,respectively.

FIG. 10 is a graph depicting octreotide serum levels in eleven humansubjects with acromegaly over six months implanted with an octreotideformulation of the present invention.

FIG. 11 is a graph depicting octreotide serum levels in two dogs oversix months implanted with an octreotide formulation of the presentinvention.

FIG. 12 is a graph depicting IGF-1 serum levels in two dogs over sixmonths implanted with an octreotide formulation of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularmolecules, compositions, methodologies or protocols described, as thesemay vary. It is also to be understood that the terminology used in thedescription is for the purpose of describing the particular versions orembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims. The termsused herein have meanings recognized and known to those of skill in theart, however, for convenience and completeness, particular terms andtheir meanings are set forth below.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art. Although anymethods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments of the presentinvention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated byreference to the extent they support the present invention. Nothingherein is to be construed as an admission that the invention is notentitled to antedate such disclosure by virtue of prior invention.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. For example,about 50% means in the range of 45%-55%.

“Controlled release formulation” refers to a formulation designed toconsistently release a predetermined, therapeutically effective amountof drug or other active agent such as a polypeptide or a syntheticcompound over an extended period of time, with the result being areduction in the number of treatments necessary to achieve the desiredtherapeutic effect. In the matter of the present invention, a controlledformulation would decrease the number of treatments necessary to achievethe desired effect in terms of decreased growth hormone levels ordecreased IGF-1 levels, or an improvement in symptoms associated withacromegaly, including but not limited to abnormal growth. The controlledrelease formulations of the present invention achieve a desiredpharmacokinetic profile in a subject, preferably commencement of therelease of the active agent substantially immediately after placement ina delivery environment, followed by consistent, sustained, preferablyzero-order or near zero-order release of the active agent.

The terms “patient” and “subject” mean all animals including humans.Examples of patients or subjects include humans, cows, dogs, cats,goats, sheep, and pigs.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compounds of the above formula, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The term “salts” refers to the relatively non-toxic, inorganic andorganic acid addition salts of compounds of the present invention. Thesesalts can be prepared in situ during the final isolation andpurification of the compounds or by separately reacting the purifiedcompound in its free base form with a suitable organic or inorganic acidand isolating the salt thus formed. Representative salts include theacetate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, tetramethylammonium, tetraethylammonium,methlyamine, dimethlyamine, trimethlyamine, triethlyamine, ethylamine,and the like. (See, for example, S. M. Barge et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein byreference.).

“Treatment” refers to the administration of medicine or the performanceof medical procedures with respect to a patient, for either prophylaxis(prevention) or to cure the infirmity or malady in the instance wherethe patient is afflicted.

A “therapeutically effective amount” is an amount sufficient todecrease, prevent, or ameliorate the symptoms associated with a medicalcondition. In the context of hormonal therapy it can also mean tonormalize body functions or hormone levels in disease or disorders. Forexample, a therapeutically effective amount of a controlled releaseformulation of octreotide is a predetermined amount calculated toachieve the desired effect, e.g., to effectively decrease growth hormoneor IGF-1 levels in a patient.

Octreotide is an octapeptide with the following amino acid sequence:L-cysteinamide,D-phenylalanyl-L-cysteiny-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic(2→7)-disulfide; [R—(R*,R*)]. The structure of octreotide is shownbelow.

The chemical formula is C₄₉H₆₆N₁₀O₁₀S₂ and its molecular weight is1019.3 Da. Its therapeutic category is gastric antisecretory agent. Theoctreotide of the present invention may exist in e.g., free form, saltform or in the form of complexes thereof. Acid addition salts may beformed with e.g. organic acids, polymeric acids and inorganic acids.Acid addition salts include e.g., the hydrochloride and acetates.Complexes are e.g., formed from octreotide on addition of inorganicsubstances, e.g., inorganic salts or hydroxides such as Ca— and Zn—salts and/or addition of polymeric organic substances. The acetate saltis the preferred salt for formulations of the present invention.

Embodiments of the present invention provide a drug delivery device thatcan achieve the following objectives: a controlled release rate (zeroorder release rate) to maximize therapeutic effects and minimizeunwanted side effects; an easy way to retrieve the device if it isnecessary to end the treatment; an increase in bioavailability with lessvariation in absorption and no first pass metabolism.

One aspect of the invention is a controlled release pharmaceuticalcomposition comprising octreotide acetate in a controlled releasehydrogel device. The composition of the present invention is capable ofproviding, upon administration to a patient, a release profile ofoctreotide extending over at least 2 months, preferably at least about 6months or more, up to about two years. Preferably octreotide iscontained within the hydrogel and the formulation releases atherapeutically effective amount of octreotide over an extended periodof time. In preferred embodiments, the hydrogel comprises a polymerselected from methacrylate based polymers, polyurethane based polymersand combinations thereof. A therapeutically effective amount is anamount of octreotide, preferably octreotide acetate, that whenadministered to a patient or subject, ameliorates a symptom ofacromegaly. In a preferred embodiment, the formulation may furtherinclude pharmaceutically acceptable excipients.

When the compositions of the present invention are administered to apatient, the concentration of octreotide in the patient's plasma overtime (release profile) may extend over a period of at least 2 months,preferably about 6 months, and up to about two years. The compositionsmay provide a mean plasma concentration at steady state of octreotide ina human patient of from about 0.1 to about 9 ng/ml, preferably about 1to about 2 ng/ml, more preferably about 1.2 to about 1.6 ng/ml. Steadystate is the point at which the amount of drug administered over adosing interval equals the amount of drug being eliminated over thatsame period.

The hydrogel may be a homogeneous homopolymer or copolymer having apredetermined equilibrium water content (EWC) value formed by thepolymerization of a mixture of ethylenically unsaturated monomer A andethylenically unsaturated monomer B, for example, 2-hydroxyethylmethacrylate (HEMA) and hydroxypropyl methacrylate (HPMA). Thepredetermined EWC may be calculated by determining the EWC values of thehydrogel homopolymer of hydrophilic monomer A (homopolymer A) and thehydrogel homopolymer of hydrophilic monomer B (homopolymer B);determining the relationship of the EWC values of the homogeneouscopolymers AB versus the chemical composition of said copolymers AB;selecting the targeted EWC value and determining the chemicalcomposition of copolymer AB having the targeted EWC value; forming apolymerizable mixture of monomer A and monomer B in amounts sufficientto yield copolymer AB having the targeted EWC value; and effect thepolymerization reaction to yield copolymer AB characterized by thetargeted EWC value.

By the expressions “copolymer AB” or “copolymer AB consists essentiallyof monomer A units and monomer B units” is meant that the additioncopolymerization of monomer A and monomer B has been effected throughthe polymerizable ethylenic bond of the said monomers. By way ofillustration, if monomer A is 2-hydroxyethyl methacrylate and monomer Bis N-methylacrylamide, copolymer AB contains recurring monomer A unitsand recurring monomer B units.

Unless the context indicates otherwise, the term “copolymer” includespolymers made by polymerizing a mixture of at least two ethylenicallyunsaturated monomers.

By the term “HEMA unit(s)” is meant the structure

recurring in the polymer obtained by polymerizing hydrophilic materialcontaining 2-hydroxyethyl methacrylate (“HEMA”).

By the term “HPMA unit(s)” is meant the structure

obtained by polymerizing hydrophilic material containing hydroxypropylmethacrylate (“HPMA”).

Liquid polymerizable material useful in the hydrophilic products includea wide variety of polymerizable hydrophilic, ethylenically unsaturatedcompounds, in particular, hydrophilic monomers such as the monoester ofan acrylic acid or methacrylic acid with a polyhydroxy compound havingan esterifiable hydroxyl group and at least one additional hydroxylgroup such as the monoalkylene and polyalkylene polyols of methacrylicacid and acrylic acid, e.g., 2-hydroxyethyl methacrylate and acrylate,diethylene glycol methacrylate and acrylate, propylene glycolmethacrylate and acrylate, dipropylene glycol methacrylate and acrylate,glycidyl methacrylate and acrylate, glyceryl methacrylate and acrylate,and the like; the 2-alkenamides, e.g., acrylamide, methacrylamide, andthe like; the N-alkyl and N,N-dialkyl substituted acrylamides andmethacrylamides such as N-methylmethacrylamide,N,N-dimethylmethacrylamide, and the like; N-vinylpyrrolidone; thealkyl-substituted N-vinylpyrrolidones, e.g., methyl substitutedN-vinylpyrrolidone; N-vinylcaprolactam; the alkyl-substitutedN-vinylcaprolactam, e.g., N-vinyl-2-methylcaprolactam,N-vinyl-3,5-dimethylcaprolactam, and the like. Acrylic and methacrylicacid can also be useful in these formulations.

Mixtures of hydrophilic monomers are employed in the polymerizationreaction. The type and proportion of monomers are selected to yield ahomogeneous polymer, preferably a crosslinked homogeneous polymer, whichon hydration possesses the desired EWC value for the contemplatedapplication or use. This value can be predetermined by preparing aseries of copolymers using different monomer ratios, e.g., mixtures ofHEMA and HPMA of varying ratios, ascertaining the EWC values of thecopolymers, and plotting the relationship of % HPMA (or % HEMA) units inthe HPMA/HEMA copolymers versus weight percent EWC of the copolymers(see FIG. 1).

In one embodiment, the hydrophilic implant as a xerogel, readily absorbswater. In a hydrated state it is referred to as a hydrogel. In eitherform, it is biocompatible and non-toxic to the host andnon-biodegradable. It is, of course, water-swellable andwater-insoluble. When the hydrogel attains its maximum level ofhydration, the water content of the hydrogel is referred to as“equilibrium water content”. The percent water content of the hydrogel(any state of hydration) is determined as follows:

$\frac{{{weight}\mspace{14mu} {of}\mspace{14mu} {hydrogel}} - {{weight}\mspace{14mu} {of}\mspace{14mu} {dry}\mspace{14mu} {polymer}\mspace{14mu} ({xerogel})}}{{weight}\mspace{14mu} {of}\mspace{14mu} {hydrogel}} \times 100$

In some instances the polymerization of certain hydrophilic monomericmixtures may result in homogeneous hydrophilic copolymers whichdissolve, to a varying extent, in an aqueous medium. In such cases, asmall amount, e.g., up to 3 percent, of a copolymerizablepolyethylenically unsaturated crosslinking agent can be included in themonomeric mixture to obtain homogeneous crosslinked copolymers which arewater-insoluble as well as water-swellable. Slightly crosslinkedhomopolymer of HEMA has a EWC value of about 38%. Crosslinked copolymersof HEMA and HPMA have EWC values below 38%. On the other hand,crosslinked copolymers of HEMA and acrylamide exhibit EWC values above38 w/v %, e.g., upwards to approximately 75 weight %, and higher.Therefore, depending on the useful or effective elution rate of theactive compound, e.g., drug, that is required of a hydrogel deliverysystem for a particular application, one skilled in the art, byfollowing the teachings disclosed herein, can tailor-make copolymerhydrogel membranes which will elute the drug at the required rate.Preferred copolymers contain about 15% to about 70 weight % of HEMAunits and from about 85 to 30 weight % of units of a second ethylenicmonomer and possess predetermined EWC values in the range of from about20% to about 75%, preferably about 25%. Highly preferred homogenouscopolymers are those made from hydrophilic monomeric mixtures containingfrom about 80 weight % HPMA, and from about 20 weight % HEMA. In furtherembodiments, the mixture may further contain a small amount of apolyethylenically unsaturated crosslinking agent, e.g.,trimethylolpropane trimethacrylate (“TMPTMA”).

Various aspects of the invention include homogeneous hydrophiliccopolymers whose homogeneous polymer structure is formed via thepolymerization of a mixture of hydrophilic monomers describedpreviously; and the drug delivery device which utilize the homogeneouspolymer cartridges in the delivery system. The polymerization of amixture of hydrophilic monomers and hydrophobic monomers yieldsheterogeneous polymers. When hydrophobic segments are present in thepolymer, the interfacial free energy increases, thus enhancing proteinadsorption and mineralization after implantation in an animal. Hydrogelsof polyHEMA were measured to have interfacial free energy close to zero.According to the interfacial free energy interpretation, hydrogels ofstrictly hydrophilic components would strongly appear to bebiocompatible with body tissue. Slightly crosslinked polyHEMA is ahomogeneous, hydrophilic “homopolymer” (disregarding the relativelysmall quantities of polymerized crosslinking agent therein) ofrelatively fixed characteristics or values. Techniques of altering the“homopolymer” polyHEMA to impart to it additional characteristics orproperties are difficult, time-consuming, and oftentimes result inerratic property behavior. On the other hand, mixtures of HEMA withvarying quantities of other polymerizable hydrophilic comonomer(s) canbe polymerized to give predictable homogeneous hydrophilic copolymershaving (predetermined) tailor-made properties.

Useful crosslinking agents which can be included in the polymerizablereaction medium include, for example, the polyethylenically unsaturatedcompounds having at least two polymerizable ethylenic sites, such as thedi-, tri- and tetra-ethylenically unsaturated compounds, in particular,the tri-unsaturated crosslinking agents with/without the di-unsaturatedcrosslinking compounds, for example, divinylbenzene, ethylene glycoldimethacrylate and diacrylate, propylene glycol dimethacrylate anddiacrylate; and the di-, tri- and tetra-acrylate or methacrylate estersof the following polyols: triethanolamine, glycerol, pentaerythritol,1,1,1-trimethylolpropane and others.

The polymerization reaction can be carried out in bulk or with an inertsolvent. Suitable solvents include water; organic solvents such aswater-soluble lower aliphatic monohydric alcohols as well as polyhydricalcohols, e.g., glycol, glycerine, dioxane, etc.; and mixtures thereof.

Compounds useful in the catalysis of the polymerizable ethylenicallyunsaturated compounds include the free-radical compounds and/orinitiators of the type commonly used in vinyl polymerization such as theorganic peroxides, percarbonates, hydrogen peroxides, and alkali metalsulfates. Illustrative examples include cumene hydroperoxide, t-butylhydroperoxide, benzoyl peroxide, bis(4-t-butylcyclohexyl)peroxydicarbonate, hydrogen peroxide, 2,4-dichlorobenzoyl peroxide,acetyl peroxide, di-n-propyl peroxydicarbonate, di-t-butyl peroxide,di-sec-butyl peroxydicarbonate, ammonium sulfate, potassium sulfate, andsodium sulfate. A preferred catalyst is one which is effective atmoderately low temperature such as at about 20°-80° C., such astert-butyl peroctoate, benzoyl peroxide, and di(secbutyl)peroxydicarbonate. A conventional redox polymerization catalyst can alsobe employed. Preferably, polymerization of the ethylenic compounds canbe effected using radiation, e.g., U.V., X-Ray, gamma radiation,microwave, or other well-know forms of radiation. A preferred catalystfor U.V. cure is benzoin methyl ether. Catalysts and/or initiatorsand/or radiation are employed in a catalytically effective amount tooptimize the polymerization reaction.

The current invention focuses on the application of polyurethane basedpolymers, thermoplastics or thermosets, to the creation of implantabledrug devices to deliver biologically active compounds at controlledrates for prolonged period of time. Polyurethane polymers are preferablymade into cylindrical hollow tubes with one or two open ends throughextrusion, (reaction) injection molding, compression molding, orspin-casting (see e.g. U.S. Pat. Nos. 5,266,325 and 5,292,515, hereinincorporated by reference in their entireties), depending on the type ofpolyurethane used.

Thermoplastic polyurethane can be processed through extrusion, injectionmolding, or compression molding. Thermoset polyurethane can be processedthrough reaction injection molding, compression molding, orspin-casting. The dimensions of the cylindrical hollow tube are verycritical and need to be as precise as possible.

Polyurethane based polymers are synthesized from multi-functionalpolyols, isocyanates and chain extenders. The characteristics of eachpolyurethane can be attributed to its structure.

Thermoplastic polyurethanes are made of macrodiols, diisocyanates, anddifunctional chain extenders (e.g., U.S. Pat. Nos. 4,523,005 and5,254,662, herein incorporated by reference in their entireties).Macrodiols make up the soft domains. Diisocyanates and chain extendersmake up the hard domains. The hard domains serve as physicalcrosslinking sites for the polymers. Varying the ratio of these twodomains can alter the physical characteristics of the polyurethanes.

Thermoset polyurethanes can be made of multifunctional (greater thandifunctional) polyols and/or isocyanates and/or chain extenders (e.g.U.S. Pat. Nos. 4,386,039 and 4,131,604, herein incorporated by referencein their entireties). Thermoset polyurethanes can also be made byintroducing unsaturated bonds in the polymer chains and appropriatecrosslinkers and/or initiators to do the chemical crosslinking (e.g.U.S. Pat. No. 4,751,133, herein incorporated by reference in itsentirety). By controlling the amounts of crosslinking sites and how theyare distributed, the release rates of the actives can be controlled.

Different functional groups can be introduced into the polyurethanepolymer chains through the modification of the backbones of polyolsdepending on the properties desired. When the device is used for thedelivery of water soluble drugs, hydrophilic pendant groups such asionic, carboxyl, ether, and hydroxy groups are incorporated into thepolyols to increase the hydrophilicity of the polymer (e.g. U.S. Pat.Nos. 4,743,673 and 5,354,835, herein incorporated by reference in theirentireties). When the device is used for the delivery of hydrophobicdrugs, hydrophobic pendant groups such as alkyl, siloxane groups areincorporated into the polyols to increase the hydrophobicity of thepolymer (e.g. U.S. Pat. No. 6,313,254, herein incorporated by referencein its entirety). The release rates of the actives can also becontrolled by the hydrophilicity/hydrophobicity of the polyurethanepolymers.

In a preferred embodiment, small cylindrically shaped implants containwithin their core octreotide, preferably octreotide acetate, andoptionally, a pharmaceutically acceptable carrier. The membranethickness (between the interior and exterior surfaces) of the implant issubstantially uniform, and serves as a rate-limiting barrier for therelease of the contained agent. Such implants can be plasticized orhydrated and reshaped into other geometrically shaped articles for usein various medical applications.

In the manufacture of the implantable formulation, several factors areconsidered. The release profile (delay time, release rate, and duration)is determined; the hydrophilic polymeric material is identified; and thediffusivity of the active agent through it (as a rate-limiting membrane)is measured. The hydration profile of the rate-limiting membrane for agiven active agent may be readily determined by preparing a film of theselected polymer and subjecting it to a diffusion study, using a twocompartment vertical glass cell, as is well known in the art.

The diffusion coefficient and the water content at which diffusionbegins (i.e., below which substantially no diffusion occurs—hereinafter“% H_(d)”) are determined. A series of membranes is prepared fromvarious polymers. The membranes are then hydrated to their capacity andtheir equilibrium water contents are measured. The fully hydratedmembranes are placed in the two-compartment, vertical glass cells tomeasure and plot the diffusion of the macromolecular composition throughthe membrane materials at the various equilibrium water contents. Theequilibrium water content of the most hydrated membrane through which nodiffusion is detected (i.e., none of the active agent diffuses into thereceptor cell) is the % H_(d) for the system being tested. This can beaccomplished by plotting a curve of the permeability verus equilibriumwater content.

The permeability results (diffusion coefficients) are obtained accordingto Fick's First Law of Diffusion, by use of the equation:

dQ/dt=APC

wherein dQ/dt is the flux through the membrane material (μg/hr); it ismeasured as the slope of the linear part of the curve of cumulativetransport versus time; wherein A is the area of the membrane (cm²);wherein P is the membrane's permeability coefficient (cm²/hr), orDK_(d), wherein D is the diffusivity of the membrane (cm²/hr), and K_(d)is the partition coefficient for the membrane/donor solution; wherein 1is the membrane thickness as measured at the end of the experiment (cm);and wherein C_(d) is the concentration of the donor solution (μg/cm³).

The release delay profile is then determined. Another series ofpolymeric membranes can be prepared, again varying the amounts ofcrosslinker and monomers. These membranes are then hydrated, but onlypartially, i.e., to a water content less than or equal to % H_(d). Thepartially hydrated membranes are placed in two-compartment verticalglass cells to measure and plot the diffusion of the active compoundthrough the membranes versus time. Buffer solutions for the donor andreceptor cells may be selected to contact the partially hydratedmembranes and further hydrate them at approximately the same rate atwhich they will hydrate in the delivery environment. The time betweencommencement of the diffusion study, i.e., addition of the active agentto the donor cell, and the detection of a pharmaceutically effectiveconcentration of the active agent in the receptor cell is the releasedelay time for that combination of polymer and initial percenthydration.

In order to determine the physical dimensions of thecylindrically-shaped device, the total amount of active agent to bedelivered must be determined. This is the product of the desired dailydosage and the duration of delivery. In preferred embodiments, theduration of delivery is at least about 2 months, more preferably about 6months, and up to about two years. The desired daily dosage is, forexample, about 10 to about 1000 μg of octreotide per day, preferablyabout 20 to about 800 μg of octreotide per day, more preferably about 30to about 300 μg of octreotide per day.

The volume of the cylindrical reservoir (core) of a cylindrically-shapeddevice is equal to πr_(i) ² h wherein r_(i) is the radius of thereservoir and h is its height. The formula for steady state release froma cylinder is:

[dQ/dt]=[2πhDK _(d) C _(d) ]/[In(r _(o) /r _(i))]

wherein r_(o) is the outside radius of the cylindrical device; andwherein C_(d) is the concentration of drug in the donor solution, i.e.,the carrier. Steady state release is obtained when C_(d) is maintainedat saturation. The thickness of the membrane needed for the desiredsustained release is, therefore, r_(o)-r_(i).

The amount of active agent employed will depend not only on the desireddaily dose but also on the number of days that dose level is to bemaintained. While this amount can be calculated empirically, the actualdose delivered is also a function of any interaction with materials andthe carrier, if employed in the device.

Once the appropriate polyurethane polymer is chosen, the next step is todetermine the best method to fabricate the cylindrically shapedimplants.

For thermoplastic polyurethanes, precision extrusion and injectionmolding are the preferred choices to produce two open-end hollow tubeswith consistent physical dimensions. The reservoir can be loaded freelywith appropriate formulations containing actives and carriers or filledwith pre-fabricated pellets to maximize the loading of the actives. Oneopen end needs to be sealed first before the loading of the formulationinto the hollow tube. To seal the two open ends, two pre-fabricated endplugs may be used. The sealing step can be accomplished through theapplication of heat or solvent or any other means to seal the ends,preferably permanently.

For thermoset polyurethanes, precision reaction injection molding orspin casting is the preferred choice depending on the curing mechanism.Reaction injection molding is used if the curing mechanism is carriedout through heat and spin casting is used if the curing mechanism iscarried out through light and/or heat. Preferably, hollow tubes with oneopen end are made by spin casting. Preferably, hollow tubes with twoopen ends are made by reaction injection molding. The reservoir can beloaded in the same way as the thermoplastic polyurethanes.

Preferably, to seal an open end, an appropriate light-initiated and/orheat-initiated thermoset polyurethane formulation is used to fill theopen end and this is cured with light and/or heat. More preferably, apre-fabricated end plug can also be used to seal the open end byapplying an appropriate light-initiated and/or heat-initiated thermosetpolyurethane formulation on to the interface between the pre-fabricatedend plug and the open end and cured it with the light and/or heat or anyother means to seal the ends, preferably permanently.

The final process involves the conditioning and priming of the implantsto achieve the delivery rates required for the actives. Depending uponthe types of active ingredient, hydrophilic or hydrophobic, theappropriate conditioning and priming media will be chosen. Water basedmedia are preferred for hydrophilic actives and oil based media arepreferred for hydrophobic actives.

To keep the geometry of the device as precise as possible, thepreferably cylindrically shaped device can be manufactured throughprecision extrusion or precision molding process for thermoplasticpolyurethane polymers, and reaction injection molding or spin castingprocess for thermosetting polyurethane polymers.

The cartridge can be made with either one end closed or both ends open.The open end can be plugged with pre-manufactured end plug to ensure asmooth end and a solid seal. The solid actives and carriers can becompressed into pellet form to maximize the loading of the actives.

To identify the location of the implant, radiopaque material can beincorporated into the delivery device by inserting it into the reservoiror by making it into end plug to be used to seal the cartridge.

In various embodiments, the novel formulation of the present inventionmay contain a pharmaceutically acceptable carrier which may include, butis not limited to, suspending media, solvents, aqueous systems, andsolid substrates or matrices.

Suspending media and solvents useful as the carrier include, forexample, oils such as silicone oil (particularly medical grade), cornoil, castor oil, peanut oil and sesame oil; condensation products ofcastor oil and ethylene oxide; liquid glyceryl triesters of a lowermolecular weight fatty acid; lower alkanols; glycols; and polyalkyleneglycols.

The aqueous systems include, for example, sterile water, saline,dextrose, dextrose in water or saline, and the like. The presence ofelectrolytes in the aqueous systems may tend to lower the solubility ofthe macromolecular drug in them.

The solid substrates or matrices include, for example, starch, gelatin,sugars (e.g., glucose), natural gums (e.g., acacia, sodium alginate,carboxymethyl cellulose), and the like. In a preferred embodiment, thepharmaceutical formulation further comprises about 2% to about 20%, morepreferably about 10% hydroxypropylcellulose.

The carrier may also contain adjuvants such as preserving, stabilizing,wetting and emulsifying agents, and the like.

The hydrating liquid useful in the practice of the invention istypically a liquid simulating the environment in which the activecompound will be released, e.g., body fluid, sterile water, tear fluid,physiological saline solution, phosphate buffer solution, and the like.While liquids other than water are useful as the hydrating liquid, thedegree to which a hydrophilic membrane is hydrated is referred to as its“water content.”

Once the cartridges are sealed on both ends with filled reservoir, theyare conditioned and primed for an appropriate period of time to ensure aconstant delivery rate.

The priming and conditioning of the drug delivery devices involves theloading of the actives (drug) into the polymer which surrounds thereservoir, and thus prevent loss of the active before the actual use ofthe implant. The conditions used for the conditioning and priming stepdepend on the active, the temperature and the medium in which they arecarried out. The conditions for the conditioning and priming may be thesame in some instances.

The conditioning and priming step in the process of the preparation ofthe drug delivery devices is done to obtain a determined rate of releaseof a specific drug. The conditioning and priming step of the implantcontaining a hydrophilic drug is preferably carried out in an aqueousmedium, more preferably in a saline solution. For hydrophobic drugs, themedium may be a plasma-like medium, including, but not limited to,cyclodextrin. The conditioning and priming steps are carried out bycontrolling three specific factors namely the temperature, the mediumand the period of time.

A person skilled in the art would understand that the conditioning andpriming step of the drug delivery device will be affected by the mediumin which the device is placed. For example, histrelin and naltrexoneimplants have been conditioned and primed in saline solution, morespecifically, conditioned in saline solution of 0.9% sodium content andprimed in saline solution of 1.8% sodium chloride content.

The temperature used to condition and prime the drug delivery device mayvary across a wide range of temperatures but, in some instances 37C, hasbeen preferably used.

The time period used for the conditioning and priming of the drugdelivery devices may vary from a single day to several weeks dependingon the release rate desired for the specific implant or drug.

A person skilled in the art will understand the steps of conditioningand priming the implants is to optimize the rate of release of the drugcontained within the implant. As such, a shorter time period spent onthe conditioning and the priming of a drug delivery device results in alower rate of release of the drug compared to a similar drug deliverydevice which has undergone a longer conditioning and priming step.

The temperature in the conditioning and priming step will also affectthe rate of release in that a lower temperature results in a lower rateof release of the drug contained in the drug delivery device whencompared to a similar drug delivery device which has undergone atreatment at a higher temperature.

Similarly, in the case of aqueous solutions, which are in some casespreferably saline solutions, the sodium chloride content of the solutionwill also determine what type of rate of release will be obtained forthe drug delivery device. More specifically, a lower content of sodiumchloride would result in a higher rate of release of drug when comparedto a drug delivery device which has undergone a conditioning and primingstep where the sodium chloride content was higher.

In one embodiment, a pharmaceutical formulation of the present inventioncomprises a formulation of octreotide acetate within a mixture of HEMAand HPMA copolymer, preferably about 20% HEMA and about 80% HPMA. Inpreferred embodiments, the pharmaceutical formulation comprises about 20to about 150 milligrams of octreotide, preferably about 40 to about 90milligrams. The formulation may further comprise between about 2 toabout 20% excipients. In one preferred embodiment, the formulationpreferably contains about 10% hydroxypropylcellulose. In anotherpreferred embodiment, the formulation preferably contains about 2%magnesium stearate.

In another embodiment, a pharmaceutical formulation of the presentinvention comprises a formulation of about 50 milligrams of octreotidewithin a mixture of HEMA and HPMA copolymer, preferably about 20% HEMAand about 80% HPMA. In a further embodiment, the formulation furthercomprises about 10% hydroxypropylcellulose and 2% magnesium stearatewith the octreotide acetate.

In another embodiment, a pharmaceutical formulation of the presentinvention comprises a formulation of about 83 mgs of octreotide within amixture of HEMA and HPMA copolymer, preferably about 40% HEMA and about60% HPMA. In a further embodiment, the formulation further comprisesabout 10% hydroxypropylcellulose and 2% magnesium stearate with theoctreotide acetate.

In a further embodiment, a pharmaceutical formulation of the presentinvention comprises a formulation of about 20 milligrams to about 150milligrams, more preferably about 40 milligrams to about 90 milligrams,of octreotide in a polyurethane based polymer.

A method of treating a disease associated with a hormonal disorder isalso provided. The method may include administering octreotide andmaintaining a plasma concentration at steady state of octreotide betweenabout 0.1 ng/ml and about 9 ng/ml over an extended period of time,preferably at least about 2 months, and more preferably about 6 monthsand up to about two years. In preferred embodiment, the plasmaconcentration at steady state of octreotide is maintained between about1 ng/ml and about 2 ng/ml, more preferably about 1.2 ng/ml to about 1.6ng/ml, over an extended period of time. Such hormonal disorders includeacromegaly or the like.

One embodiment is a method of decreasing GH levels by administeringoctreotide and maintaining a steady state plasma concentration ofoctreotide between about 0.1 ng/ml and about 9 ng/ml, preferably about 1ng/ml to about 2 ng/ml, more preferably about 1.2 to about 1.6 ng/ml,over an extended period of time, preferably at least about 2 months, andmore preferably about 6 months, and up to about two years.

Another embodiment is a method of decreasing IGF-1 levels byadministering octreotide and maintaining a plasma concentration ofoctreotide between about 0.1 ng/ml and about 9 ng/ml, preferably about 1ng/ml to about 2 ng/ml more preferably about 1.2 to about 1.6 ng/ml,over an extended period of time, preferably at least about 2 months, andmore preferably about 6 months, and up to about two years.

Another embodiment is a method of treating acromegaly comprisingadministering at least one implant of the present invention, preferablytwo implants, of the present invention. In the method, each implantadministered may contain between about 20 to about 150 milligrams ofoctreotide, preferably about 40 to about 90 milligrams of octreotide,more preferably about 50 milligrams of octreotide, and release atherapeutically effective amount of octreotide over a period of at leasttwo months, preferably about six months, and up to about two years.

Another embodiment is a method of treating symptoms associated withcarcinoid tumors and VIPomas. In one embodiment, a method of treatingsevere diarrhea and flushing episodes associated with carcinoid tumorsby administering an implantable formulation of octreotide, whichreleases a therapeutically effective amount of octreotide over at leastabout 2 months, preferably about 6 months and up to about two years. Inanother embodiment, a method of treating watery diarrhea associated withVIPomas by administering an implantable formulation of octreotide, whichrelease a therapeutically effective amount of octreotide over at leastabout two months, preferably about 6 months and up to about two years.

Another aspect is a therapeutic composition of a hydrogel andoctreotide, wherein, upon implantation, the octreotide is released at arate that provides and/or maintains a C_(ss) of about 0.1 ng/ml to about9 ng/ml, preferably about 1 ng/ml to about 2 ng/ml, more preferablyabout 1.2 ng/ml to about 1.6 ng/ml. A further embodiment is atherapeutic composition of a hydrogel and octreotide, wherein, uponimplantation, the octreotide is released at a rate of from about 10 μgto about 1000 μg per day over an extended period of time, preferablyabout 20 μg to about 800 μg, more preferably about 30 μg to about 300 μgper day. In preferred embodiments, the octreotide is release over atleast about two months, more preferably about six months, up to abouttwo years. The hydrogel may comprise methacrylate based polymers orpolyurethane based polymers.

Another embodiment is a controlled release formulation comprisingoctreotide and a hydrophilic polymer, which permits release of theoctreotide at a rate of about 30 μg to about 250 μg per day over atleast about two months, more preferably about six months to about twoyears in vitro, more preferably about 100 μg to about 130 μg per day. Ina further embodiment, the hydrophilic polymer of the formulation permitsrelease of octreotide at an average rate of about 100 μg per day invitro. Preferably, the hydrophilic polymer is selected from polyurethanebased polymers and methacrylate based polymers.

A further embodiment of the present invention is a controlled releaseformulation comprising octreotide for implantation, wherein theformulation comprises octreotide in a hydrophilic polymer effective topermit in vitro release of no more than about 20% of said octreotidefrom the formulation after about 6 weeks; and about 60% of saidoctreotide from said formulation after about six months.

The amount of a pharmaceutically acceptable ocreotide, salt, solvated,or prodrug thereof included in the pharmaceutical composition of thepresent invention will vary, depending upon a variety of factors,including, for example, the specific octreotide used, the desired dosagelevel, the type and amount of hydrogel used, and the presence, types andamounts of additional materials included in the composition. The amountof octreotide, or a derivative thereof, in the formulation variesdepending on the desired dose for efficient drug delivery, the molecularweight, and the activity of the compound. The actual amount of the useddrug can depend on the patient's age, weight, sex, medical condition,disease or any other medical criteria. The actual drug amount isdetermined according to intended medical use by techniques known in theart. The pharmaceutical dosage formulated according to the invention maybe administered about once every six months as determined by theattending physician.

Typically, the octreotide is formulated in the implant or otherpharmaceutical composition in amounts of about 20 milligrams to about150 milligrams, preferably about 40 to about 90 milligrams ofoctreotide, more preferably about 50 to about 85 milligrams. For adults,the daily dose for treatment of acromegaly is typically about 300 toabout 600 μg of immediate release octreotide per day (100 or 200 μgSandostatin® t.i.d.) Preferably, the amount of octreotide in thecomposition is formulated to release from about 10 μg to about 1000 μgper day over an extended period of time, preferably about 20 μg to about800 μg per day, more preferably about 30 μg to about 300 μg per day.Such release rates maintain desired therapeutic levels in the patient'sblood at about 0.1 to about 9 ng/ml over an extended period of time.

The hydrogel device in which octreotide is contained provides acontrolled release of octreotide into the plasma of the patient.Hydrogels suitable for controlling the release rate of octreotide foruse in the pharmaceutical compositions of the present invention includepolymers of hydrophilic monomers, including, but not limited to HPMA,HEMA and the like. Such hydrogels are also capable of preventingdegradation and loss of octreotide from the composition.

In one embodiment, a pharmaceutical formulation of the present inventioncomprises octreotide acetate contained within a hydrophilic copolymer of2-hydroxyethyl methacrylate and hydroxypropyl methacrylate. In apreferred embodiment, the copolymer of the pharmaceutical formulationcomprises about 20% HEMA and about 80% HPMA. In another preferredembodiment, the copolymer of the pharmaceutical formulation comprisesabout 40% HEMA and about 60% HPMA.

In further embodiments, the hydrogel comprises polyurethane basedpolymers.

The amount of the hydrogel included in the pharmaceutical composition ofthe present invention will vary depending upon a variety of factors,including, for example, the specific matrix used, its molecular weight,its hydrophilicity, the type and amount of octreotide used, and thepresence, types and amounts of additional materials included in thecomposition.

The size, shape and surface area of the implant may also be modified toincrease or decrease the release rate of octreotide from the implant.

The formulations of the present invention exhibit a specific, desiredrelease profile which maximizes the therapeutic effect while minimizingadverse side effects. The desired release profile may be described interms of the maximum plasma concentration of the drug or active agent(C_(max)) and the plasma concentration of the drug or active agent atsteady state (C_(ss)).

The pharmaceutical composition of the present invention can include alsoauxiliary agents or excipients, for example, glidants, dissolutionagents, surfactants, diluents, binders including low temperature meltingbinders, disintegrants and/or lubricants. Dissolution agents increasethe dissolution rate of octreotide from the dosage formulation and canfunction by increasing the solubility of octreotide. Suitabledissolution agents include, for example, organic acids such as citricacid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, aceticacid, malic acid, glutaric acid and adipic acid, and may be used aloneor in combination. These agents may also be combined with salts of theacids, e.g. sodium citrate with citric acid, in order to produce abuffer system.

Other agents that may alter the pH of the microenvironment ondissolution and establishment of a therapeutically effective plasmaconcentration profile of octreotide include salts of inorganic acids andmagnesium hydroxide. Other agents that may be used are surfactants andother solubilizing materials. Surfactants that are suitable for use inthe pharmaceutical composition of the present invention include, forexample, sodium lauryl sulphate, polyethylene stearates, polyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives,polyoxyethylene alkyl ethers, benzyl benzoate, cetrimide, cetyl alcohol,docusate sodium, glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, lecithin, medium chain triglycerides, monoethanolamine,oleic acid, poloxamers, polyvinyl alcohol and sorbitan fatty acidesters.

Diluents that are suitable for use in the pharmaceutical composition ofthe present invention include, for example, pharmaceutically acceptableinert fillers such as microcrystalline cellulose, lactose, sucrose,fructose, glucose dextrose, or other sugars, dibasic calcium phosphate,calcium sulfate, cellulose, ethylcellulose, cellulose derivatives,kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugaralcohols, dry starch, saccharides, dextrin, maltodextrin or otherpolysaccharides, inositol or mixtures thereof. The diluent is preferablya water-soluble diluent. Examples of preferred diluents include, forexample: microcrystalline cellulose such as Avicel PH112, Avicel PH101and Avicel PH102 available from FMC Corporation; lactose such as lactosemonohydrate, lactose anhydrous, and Pharmatose DCL 21; dibasic calciumphosphate such as Emcompress available from Penwest Pharmaceuticals;mannitol; starch; sorbitol; sucrose; and glucose. Diluents are carefullyselected to match the specific composition with attention paid to thecompression properties. The diluent is preferably used in an amount ofabout 2% to about 80% by weight, preferably about 20% to about 50% byweight, of the controlled release composition.

Glidants are used to improve the flow and compressibility of ingredientsduring processing. Suitable glidants include, for example, colloidalsilicon dioxide, a sub-micron fumed silica that can be prepared by, forexample, vapor-phase hydrolysis of a silicon compound such as silicontetrachloride. Colloidal silicon dioxide is a sub-micron amorphouspowder which is commercially available from a number of sources,including Cabot Corporation (under the tradename Cab-O-Sil); Degussa,Inc. (under the tradename Aerosil); and E.I. DuPont & Co. Colloidalsilicon dioxide is also known as colloidal silica, fumed silica, lightanhydrous silicic acid, silicic anhydride, and silicon dioxide fumed,among others. In one embodiment, the glidant comprises Aerosil 200.

Another agent that may be used is a surfactant, dissolution agent andother solubilizing material. Surfactants that are suitable for use inthe pharmaceutical composition of the present invention include, forexample, sodium lauryl sulphate, polyethylene stearates, polyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives,polyoxyethylene alkyl ethers, benzyl benzoate, cetrimide, cetyl alcohol,docusate sodium, glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, lecithin, medium chain triglycerides, monoethanolamine,oleic acid, poloxamers, polyvinyl alcohol and sorbitan fatty acidesters. Dissolution agents increase the dissolution rate of octreotideand function by increasing the solubility of the octreotide. Suitabledissolution agents include, for example, organic acids such as citricacid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, aceticacid, malic acid, glutaric acid and adipic acid, which may be used aloneor in combination. These agents may also be combined with salts of theacids, e.g. sodium citrate with citric acid, in order to produce abuffer system. Other agents that may be used to alter the pH of themicroenvironment on dissolution include salts of inorganic acids andmagnesium hydroxide.

Disintegrants that are suitable for use in the pharmaceuticalcomposition of the present invention include, for example, starches,sodium starch glycolate, crospovidone, croscarmellose, microcrystallinecellulose, low substituted hydroxypropyl cellulose, pectins, potassiummethacrylate-divinylbenzene copolymer, poly(vinyl alcohol), thylamide,sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, betacyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite andmixtures thereof.

The active ingredient of the present invention may be mixed withexcipients which are pharmaceutically acceptable and compatible with theactive ingredient and in amounts suitable for use in the therapeuticmethods described herein. Various excipients may be homogeneously mixedwith octreotide of the present invention as would be known to thoseskilled in the art. For example, octreotide may be mixed or combinedwith excipients such as but not limited to microcrystalline cellulose,colloidal silicon dioxide, lactose, starch, sorbitol, cyclodextrin andcombinations of these.

Lubricants that are suitable for use in the pharmaceutical compositionof the present invention include agents that act on the flowability ofthe powder to be compressed include but are not limited to silicondioxide such as Aerosil 200, talc; stearic acid, magnesium stearate,calcium stearate, hydrogenated vegetable oils, sodium benzoate, sodiumchloride, leucine carbowax, magnesium lauryl sulfate, and glycerylmonostearate.

According to another aspect of the invention, there is provided astable, controlled-release implantable dosage formulation which includesan effective amount a octreotide in a hydrogel, and which, uponadministration to a patient or as part of a therapy regimen, provides arelease profile (of therapeutically effective blood plasma level ofoctreotide) extending for a period of at least about 2 months,preferably about 6 months, and up to about two years.

The dosage formulation of the present invention may comprise also one ormore pharmaceutically acceptable excipients as mentioned above. Inpreferred embodiments, the dosage formulation will comprise diluents anda lubricant in addition to octreotide unit dose and the rate-controllingpolymer. A particularly preferred excipient is magnesium stearate. Whenthese materials are used, the magnesium stearate component preferablycomprises from about 0.5 to about 5% w/w of the dosage formulation, morepreferably about 2%, and the hydrogel and octreotide comprise thebalance of the formulation.

Another preferred excipient is hydroxypropylcellulose. When used, thehydroxypropylcellulose component preferably comprises from about 0.5 toabout 20% w/w of the dosage formulation, more preferably about 10%, andthe hydrogel and octreotide comprise the balance of the formulation.

In a preferred embodiment, the formulation comprises both magnesiumstearate and hydroxypropylcellulose, preferably about 2% magnesiumstearate and about 10% hydroxypropylcellulose and the hydrogel andoctreotide comprise the balance of the formulation.

As used herein, the term “controlled release” includes thepredetermined, consistent release of active agent from the dosageformulation at a rate such that a therapeutically beneficial blood levelbelow toxic levels of the active agent is maintained over a period of atleast about 2 months, preferably about 6 months or more. Preferably, theamount of active agent in the implantable formulation establish atherapeutically useful plasma concentration through administration ofthe pharmaceutical composition every at least about two months,preferably about every six months, up to about two years.

The compositions of the present invention may be used for the treatmentof hormonal diseases characterized by increased levels of GH and IGF-1by administering to a patient an implantable formulation of the presentinvention. Preferably, the implant is administered every about sixmonths, and releases a therapeutically effective amount of octreotide,preferably octreotide acetate. The implantable composition releases aconcentration of octreotide in the patient at about the minimumtherapeutically effective level to ameliorate the hormonal disorder, yetrelatively lower compared to the maximum concentration in order toenhance restful periods for the patient during the day. The compositionsmay be administered to a subject at a dose and for a period sufficientto allow said subject to tolerate said dose without showing any adverseeffects and thereafter increasing the dose of said active agent, ifneeded, at selected intervals of time until a therapeutic dose isachieved in the subject. For example, the active agent is preferablyadministered at a dose of from about 10 μg to about 1000 μg, preferablyabout 20 μg to about 800 μg, more preferably about 30 μg to about 300μg, of octreotide daily for a period of at least about two months, morepreferably about six months, up to about two years.

Compositions of the present invention where the octreotide is octreotideacetate are particularly suitable for use in the treatment of hormonaldisorders which are characterized by increased levels of GH and IGF-1,more especially acromegaly. The octreotide acetate agent in accordancewith the invention is also suitable for the treatment of symptomsassociated with carcinoid syndrome and VIPomas.

As discussed above, prior to implantation, the implantable formulationsmay be hydrated or “primed” for a predetermined period of time. Suitablehydrating agents include, but are not limited to, water and otheraqueous based solutions, including, but not limited to, saline and thelike. The implantable formulations may be primed for less than one dayup to a few months or longer. It has been observed that the step ofpriming affects the release of the active ingredient upon implantation.For example, priming enables the active ingredient to begin toinfiltrate and saturate the walls of the hydrogel and potentially beginto leach out of the hydrogel prior to implantation depending upon theamount of time the implant is primed. A primed implant will begin torelease active ingredient substantially upon implantation, and mayresult in a peak release of the drug shortly after implantation. Incontrast, little to no priming may result in substantially no release ofthe active ingredient upon implantation for a period of time until theimplant becomes hydrated and the active ingredient begins to bereleased.

In one embodiment, a method of administering a controlled releaseoctreotide formulation comprises hydrating an octreotide formulation ofthe present invention for one month or less, preferably for one week orless and implanting into a patient.

In a further embodiment, a method of administering a controlled releaseoctreotide formulation comprises implanting a dehydrated octreotideformulation of the present invention into a patient.

Additional features and embodiments of the present invention areillustrated by the following non-limiting examples.

EXAMPLE 1 In Vitro Octreotide Release Rates

This example illustrates preparation of implantable octreotideformulations of the present invention and their in vitro release ofoctreotide. In the present study, a series of implants were tested todetermine stability and in vitro release characteristics of octreotidefrom the hydrogel formulations over about 22 weeks (No. 146), 28 weeks(No. 136) and 33 weeks (all other formulations). Each implant containedabout 50 milligrams of octreotide acetate and about 2% stearic acid, butthe polymer cartridges contained different amounts of HEMA and HPMA andtherefore exhibited different % EWCs, as depicted in Table 1.

TABLE 1 Formulation % % % Number HEMA HPMA EWC Excipients/OtherIngredients 146 0 99.5 22.9 2% stearic acid 145 10 89.5 23.4 2% stearicacid 147 15 84.5 24.4 2% stearic acid 133 20 79.5 25.2 2% stearic acid144 25 74.5 25.6 2% stearic acid 143 30 69.5 26.1 2% stearic acid 142 3564.5 26.6 2% stearic acid 136 40 59.5 27.6 2% stearic acid

FIGS. 2, 3 and 4 depict the release of octreotide from the implant perday for each of the formulations provided above. As noted in FIG. 2, theinitial release was relatively high and dropped relatively quickly forFormulation No. 136. As shown in FIG. 3, the initial release rate forFormulation No. 146 was relatively low. FIG. 4 presents the releaseprofiles for Formulation Nos. 145, 147, 133, 144, 143 and 142. As shownin FIG. 4, the initial release rates show a good relationship with the %EWC, ranging from 20 to 450 μg per day for % EWCs of 22.9 to 27.6%.However problems were encountered with respect to the osmotic pressuredifferential within the implant and the elution media. Therefore inorder to stabilize the octreotide formulations a number of experimentswere designed using excipients which would provide better stabilitybased on a “preferential hydration” principle.

EXAMPLE 2 Formulation Study in Calf Serum

To determine the effect of osmotic pressure on the swelling problem twoimplants of the present invention corresponding to Formulation No. 136and Formulation No. 143 were eluted in calf serum. In particular,Formulation No. 136, composed of about 40% HEMA and 60% HPMA, containingoctreotide acetate with 2% stearic acid and Formulation No. 143,composed of about 30% HEMA and 70% HPMA, containing a mixture of 20%PEG3300 and 80% octreotide acetate, were tested. After three months, theimplants exhibited normal appearance, being relatively straight and onlyslightly swollen.

EXAMPLE 3 Formulation Study

Due to osmotic pressure differential the implants described in example 1were seen to swell significantly ultimately resulting in bursting of theimplants. This example illustrates formulations designed to screenagents useful in stabilization of the octreotide implant. In the presentstudy, a series of implants was monitored to determine the effect ofexcipient on implant shape and durability. Each of the polymercartridges was composed of about 28% HEMA, about 66.5% HPMA and 5%glycerin. The contents contained octreotide acetate with variousexcipients, as shown in Table 2.

TABLE 2 Sample No. Excipients/Other Ingredients 1 None 2 20% PEG 3300 340% PEG 3300 4  2% Stearic acid (control) 5 10% Glycolic acid 6 20%Poly(lactic acid) 7 10% Mannitol 8 10% MCC (microcrystalline cellulose)9 20% MCC 10 10% Sesame oil

Hydrophobic agents such as sesame oil and MCC separated in theformulation and did not provide “preferential hydration” and were lesspreferable in accordance with the present invention. Hydrophilic agentslike PEG 3300 increased the osmotic pressure differential and increasedswelling. Low molecular weight additives like mannitol and glycolic aciddid not provide a stabilizing effect and resulted in a decrease inintegrity. None of these agents provided satisfactory stabilization ofthe octreotide formulations. Therefore a second study, shown in Example4, was initiated.

EXAMPLE 4 Formulation Study and In Vitro Octreotide Release Rates

This study was conducted to evaluate stability of octreotide in hydrogelimplants using various excipients as shown in Table 3. The excipientswere chosen to have high molecular weight and some hydrophilic nature.Each implant was made from polymer cartridges composed of about 20% HEMAand about 80% HPMA. The appearance of the implants in saline wasmonitored and rated over the course of nine weeks. The results are shownin Table 3.

TABLE 3 Implant Appearance Formulation at 9 Weeks No. Excipients/OtherIngredients (see key below) 133 20% Dextran 3 133 20% TPGS (vitamin Ederivative) 2 133 20% HEC (hydroxyethyl cellulose) 3 133 20% HPC(hydroxypropyl cellulose) 2 133 20% Albumin 2 133 20% Pectin 2 133 20%AcDiSol 1.5 133 20% Carbopol 1 133  2% SA (stearic acid) - control 40-straight, no swelling, 1-straight with some swelling, 2-slight bendingwith some swelling 3-bent and swollen, 4-bent with significantdeformation

As depicted in FIG. 5, the formulation containing dextran had thehighest elution rate. The formulations containing pectin, AcDiSol andCarbopol exhibited less than satisfactory release after two weekshydration and nine weeks elution. Accordingly, a preferred embodimenthaving superior stabilizing effect, combination of good elution andappearance, was achieved with hydroxypropylcellulose.

EXAMPLE 5 1-Month Implantation Study in a Healthy Dog

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. A healthy dog was implanted with one octreotide subdermalimplant of the present invention. The octreotide subdermal implantformulation had a water content of 26.6%, containing 44 mg octreotideacetate. In vitro release rates were estimated at about 500 μg/day inweek 1 and decreasing to about 300 μg/day in week 4 for a total releaseof about 10 mg of octreotide over the duration of the study. The implantwas removed at 28 days after implantation. The implant used in thisstudy was about 3.5 cm in length. Blood samples (1.5 ml) to obtain theserum concentration of octreotide acetate, IGF-1 and GH were obtained ondays 0, 1-7, 11, 14, 18, 21, 25 and 28 via jugular puncture withoutanesthesia and without fasting.

Clinical observations included that the octreotide implant formulationwas well tolerated, food intake was normal, and no abnormal behavior wasnoted.

Serum analysis showed a peak of octreotide acetate at day 4 anddetectable amounts of octreotide acetate at all intervals measured.IGF-1 concentrations decreased after implantation until day 4, thenreturned to predose levels by day 25. IGF-1 levels declined from 40 to90% of pre-implantation level, as can be seen in FIG. 6.

EXAMPLE 6 6-Month Implantation Study in Six Healthy Dogs

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. Six healthy dogs were divided into two groups andimplanted with one or two octreotide subdermal implants of the presentinvention, respectively. The octreotide subdermal implants had a watercontent of about 25.2% and contained about 60 mg octreotide acetate. Theimplants were removed six months after implantation. Blood samples (10ml) to obtain the serum concentration of octreotide acetate, IGF-1 andGH were obtained once daily for the first 7 days following implantationfollowed by twice a week sampling for three weeks, and then once a weekuntil conclusion of the six month period. Four days prior toimplantation, baseline serum samples were taken as a control.

Results indicate octreotide serum levels ranged from 200 to 700 pg/ml indogs receiving one implant and 400 to 1000 pg/ml in dogs receiving twoimplants. IGF-1 levels were reduced as much as 90% in both treatmentgroups as can be seen in FIGS. 7 and 8. Measurement of serum GH levelswas abandoned after about the first month of the study because levels inhealthy animals are too low to detect further reductions. Clinicalobservations included the octreotide implant formulation was welltolerated, food intake was normal, and no abnormal behavior was noted.

EXAMPLE 7 6-Month Implantation Study in Humans

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. A six-month study was conducted in eleven patients withacromegaly. One or two implants of the present invention were implantedsubcutaneously in 11 patients diagnosed with acromegaly, who werepreviously treated with a commercially available octreotide LARformulation. Levels of GH and IGF-1 were measured at baseline and everymonth thereafter for a period of six months. Each implant containedapproximately 60 mg of octreotide acetate in a copolymer of 20% HEMA and79.5% HPMA, with an EWC of about 25.2%. The implants used in this studywere about 44 mm in length in a dry state and 50 mm in length in ahydrated state. The diameters of the implants were about 2.8 mm in a drystate and about 3.5 to about 3.6 mm in a hydrated state. The implantswere hydrated for a period of about 1 week prior to implantation.

The reference ranges for GH is up to 2.5 mg/L, age-independent. Table 4,below, illustrates the basal levels of GH in mg/L over six months afterimplantation of octreotide implants of the present invention. PatientNo. 11 did not participate in the study due to failure to meet screeningcriteria.

TABLE 4 Basal GH Levels Visit 1 (implant Visit 2 Visit 3 Visit 4 Visit 5Visit 6 Visit 7 # of Insertion) (Month 1) (Month 2) (Month 3) (Month 4)(Month 5) (Month 6) Implants Screening Basal GH Basal GH Basal GH BasalGH Basal GH Basal GH Basal GH Patient # Age Received GH (mg/L) (mg/L)(mg/L) (mg/L) (mg/L) (mg/L) (mg/L) (mg/L) 001 39 1 26 16.3 0.9 1.5 1.11.1 1.1 2.1 002 38 2 17.8 20.7 1.4 0.2 0.3 0.2 0.3 0.48 003 49 1 67 552.8 3.1 3.3 5.0 5.3 5.8 004 47 2 7.9 7 2.6 3.8 2.8 3.7 4.0 2.4 005 43 110.8 11 2.2 1.8 2.2 1.6 2.2 1.3 006 43 1 1.7 1.7 1.8 2.3 1.9 1.7 1.8 1.9007 30 2 23.3 21.8 2.4 2.2 2.9 2.0 1.1 0.51 008 58 2 1.9 3.2 0.1 0.1 2.00.1 0.6 0.11 009 47 2 14.9 14.1 1.4 0.9 1.5 1.1 1.4 1.4 010 78 1 4 5.20.4 0.2 0.5 0.2 0.3 1.0 012 40 2 21.1 27.8 13.5 13.7 14 11.9 8.9 13.1mean 16.7 2.7 2.7 3.0 2.6 2.7 2.7

As shown above, by month six 89% of subjects exhibited normalized growthhormone levels.

Reference ranges for IGF-1 is as follows: (i) 17-24 years old is about180-780 ng/mL; (ii) 25-39 years old is about 114-400 ng/mL; (iii) 40-54years old is about 90-360 ng/mL; and (iv) >54 years old is about 70-290ng/mL. Table 5, below, illustrates the basal levels of IGF-1 in ng/mlover six months after implantation of octreotide implants of the presentinvention.

TABLE 5 Serum levels of IGF-1 Visit 1 (implant Visit 2 Visit 3 Visit 4Visit 5 Visit 6 Visit 7 # of Screening Insertion) (Month 1) (Month 2)(Month 3) (Month 4) (Month 5) (Month 6) Implants IGF-1 IGF-1 IGF-1 IGF-1IGF-1 IGF-1 IGF-1 IGF-1 Patient # Age Received (ng/mL) (ng/mL) (ng/mL)(ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL) 001 39 1 1500 1500 820 600 900880 790 750 002 38 2 1700 1300 210 180 190 170 130 230 003 49 1 11001200 610 550 750 660 850 660 004 47 2 1700 1800 1100 1200 1200 1100 910990 005 43 1 1100 1000 450 510 480 600 490 430 006 43 1 520 580 470 430440 480 440 460 007 30 2 1900 1700 440 560 560 600 430 520 008 58 2 17001200 220 240 170 260 160 240 009 47 2 2200 1800 590 830 950 930 11001100 010 78 1 590 490 270 260 230 310 220 350 012 40 2 1600 1600 13001500 1400 1700 1500 1400 mean 1288 589 624 661 699 602 648

As shown above, by month six, 22% of subjects exhibited a normalizedIGF-1 level.

FIGS. 9A and 9B demonstrate a comparison of the octreotide implant ofthe present invention with a commercially available formulation ofoctreotide acetate and the efficacy of the implant appeared to be atleast as good as that of the commercially available octreotide LARformulation. The therapeutic effect of these implants continuedsuccessfully for the entire 6 months of the study duration.

IGF-1 levels were decreased in all patients, with normalization in 2patients. The decrease was already observed at one month of therapy andthe mean IGF-1 level was stable for the following 5 months. A comparisonwith decreases previously observed in the same patients while on thecommercially available octreotide LAR formulation therapy was possiblein 8 of the 9 patients. In 6 of the 8 patients, the percentage decreasein IGF-1 during the implant was greater than that while on thecommercially available octreotide LAR formulation, whereas in 2, it wasless. After 6 months of therapy with the implant, GH levels in 3patients were <1 ng/ml and in another 5, were <2.5 ng/ml. This comparedfavorably with the results on the commercially available octreotide LARformulation, where GH levels in only 2 patients were <1 ng/ml and inanother 2, were under 2.5 ng/ml.

Levels of octreotide in the serum of patients was also measured, asshown in Table 6, below.

TABLE 6 Octreotide Serum Levels Month 1 2 3 4 5 6 7 # Implants PatientID Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Gender 1Patient 1 1181 874.5 738.0 894.3 699.2 722.3 169.0 F 2 Patient 2 26862478 1625 1833 1388 1203 280 M 1 Patient 3 2570 2351 1332 980.5 1131775.2 173 F 2 Patient 4 4268 3308 2582 2650 2455 1984 166 M 1 Patient 51218 1022 610.0 783.2 709.4 545.8 144 F 1 Patient 6 1899 1445 1427 11231148 747.7 206 F 2 Patient 7 5524 2621 3656 3141 2205 1466 154 F 2Patient 8 8684 3387 4899 3336 3454 1765 170 F 2 Patient 9 3850 860.62638 1766 1729 1510 203 M 1 Patient 10 2055 1628 1192 863.9 1641 12311130 F 2 Patient 12 2527 1366 2006 962.8 1484 1156 189 M *Patient 10 didnot have the implant removed at visit 7

A comparison of the octreotide levels achieved with one and two implantsis depicted in the graph in FIG. 10.

Overall, results indicated that the octreotide implant of the presentinvention is at least as effective as the commercially available LARformulation of octreotide acetate in reducing GH levels and IGF-1 levelsin patients with acromegaly.

EXAMPLE 8

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. Two healthy dogs were implanted with one octreotidesubdermal implant of the present invention. The implants were nothydrated prior to implantation. The octreotide subdermal implants werecomposed of about 59.5% HPMA and about 40% HEMA and had an equilibriumwater content of about 27.6%. The implants contained about 84 mg ofoctreotide acetate, hydroxypropylcellulose and magnesium stearate. Theimplants were removed 6 months after implantation. Blood samples (10 ml)to obtain the serum concentration of octreotide acetate and IGF-1 wereobtained once daily every other day for the first four weeks followingimplantation followed by twice a week sampling for four weeks, and thenonce a week until conclusion of the 6 month period. Two days prior toimplantation, baseline serum samples were taken as a control.

FIG. 11 shows the octreotide levels in the serum of the dogs and FIG. 12shows the levels of IGF-1 in the dogs.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontain within this specification.

1. A method of treating a patient suffering from a condition associatedwith carcinoid tumors or suffering from one or more symptoms associatedwith such condition, said method comprising: implanting subcutaneouslyinto a patient in need thereof at least one implant comprising ahydrogel and a pharmaceutical formulation comprising octreotide; whereinsaid pharmaceutical formulation is contained within said hydrogel, whichhydrogel comprises a copolymer obtained from the copolymerization of amixture comprising at least two hydrophilic, ethylenically unsaturatedmonomers; wherein said pharmaceutical formulation contains between about20 to about 150 milligrams of octreotide, in free form or salt form;wherein said pharmaceutical formulation further comprises an effectiveamount of hydroxypropylcellulose; and wherein said at least one implantreleases a therapeutically effective amount of said octreotide to saidpatient over a period of at least about two months.
 2. The method ofclaim 1, wherein said effective amount of said octreotide provides an invivo average C_(ss) in said patient of about 0.1 ng/ml to about 9 ng/mlof octreotide.
 3. The method of claim 1, wherein said pharmaceuticalformulation contains from about 40 to about 90 milligrams of octreotide.4. The method of claim 1, wherein said octreotide is octreotide acetate.5. The method of claim 4, wherein said pharmaceutical formulationcontains about 50 milligrams of said octreotide acetate.
 6. The methodof claim 4, wherein said pharmaceutical formulation contains about 80milligrams of said octreotide acetate.
 7. The method of claim 2, whereinsaid effective amount of said octreotide provides an in vivo averageC_(ss) in said patient of about 1 ng/ml to about 2 ng/ml of octreotide.8. The method of claim 1, wherein said at least one implant releases atherapeutically effective amount of octreotide over a period of abouttwo months to about two years.
 9. The method of claim 1, wherein said atleast one implant releases a therapeutically effective amount of saidoctreotide over about six months.
 10. The method of claim 1, whereinsaid at least two hydrophilic, ethylenically unsaturated monomers are2-hydroxyethyl methacrylate and hydroxypropyl methacrylate.
 11. Themethod of claim 1, wherein said copolymer comprises about 20% of2-hydroxyethyl methacrylate and about 80% hydroxypropylmethacrylate. 12.The method of claim 1, wherein the pharmaceutical formulation containsabout 0.5 to 20% w/w of the hydroxypropylcellulose
 13. The method ofclaim 1, wherein said pharmaceutical formulation further comprisesmagnesium stearate.
 14. The method of claim 13, wherein thepharmaceutical formulation contains about 0.5 to 5% w/w of the magnesiumstearate.
 15. The method of claim 1, wherein said at least one implantreleases said octreotide at a rate of about 10 ug to about 1000 ug perday over a period of about six months.
 16. The method of claim 1,wherein said at least one implant is two or more implants.
 17. Themethod of claim 1, wherein said at least one implant releases saidoctreotide at a rate of about 30 μg to about 250 μg per day in vitro.18. The method of claim 1, wherein the at least one implant is implantedin a dry state.
 19. The method of claim 1, wherein the at least oneimplant is implanted in a hydrated state.
 20. A method of treating apatient suffering from a condition associated with overproduction ofgrowth hormone or IGF-1 or suffering from one or more symptomsassociated with such condition, said method comprising: implantingsubcutaneously into a patient in need thereof at least one implantcomprising a hydrogel and a pharmaceutical formulation comprisingoctreotide; wherein said pharmaceutical formulation is contained withinsaid hydrogel, which hydrogel comprises a copolymer obtained from thecopolymerization of a mixture comprising at least two hydrophilic,ethylenically unsaturated monomers; wherein said pharmaceuticalformulation contains between about 20 to about 150 milligrams ofoctreotide, in free form or salt form; wherein said pharmaceuticalformulation further comprises an effective amount ofhydroxypropylcellulose; and wherein said at least one implant releases atherapeutically effective amount of said octreotide to said patient overa period of at least about two months.
 21. The method of claim 20,wherein said effective amount of said octreotide provides an in vivoaverage C_(ss) in said patient of about 0.1 ng/ml to about 9 ng/ml ofoctreotide.
 22. The method of claim 20, wherein said pharmaceuticalformulation contains from about 40 to about 90 milligrams of octreotide.23. A method of treating a patient suffering from a condition associatedwith VIP-secreting tumors or suffering from one or more symptomsassociated with such condition, said method comprising: implantingsubcutaneously into a patient in need thereof at least one implantcomprising a hydrogel and a pharmaceutical formulation comprisingoctreotide; wherein said pharmaceutical formulation is contained withinsaid hydrogel, which hydrogel comprises a copolymer obtained from thecopolymerization of a mixture comprising at least two hydrophilic,ethylenically unsaturated monomers; wherein said pharmaceuticalformulation contains between about 20 to about 150 milligrams ofoctreotide, in free form or salt form; wherein said pharmaceuticalformulation further comprises an effective amount ofhydroxypropylcellulose; and wherein said at least one implant releases atherapeutically effective amount of said octreotide to said patient overa period of at least about two months.
 24. The method of claim 23,wherein said effective amount of said octreotide provides an in vivoaverage C_(ss) in said patient of about 0.1 ng/ml to about 9 ng/ml ofoctreotide.
 25. The method of claim 23, wherein said pharmaceuticalformulation contains from about 40 to about 90 milligrams of octreotide.